Proposal Summary Anemia is the most common blood disorder in the world affecting an estimated 5.6% of Americans and 24.6% of the global population. Anemia is characterized by insufficient hemoglobin or red blood cells, leading to decreased blood oxygen content. Severe chronic anemia results from the hemoglobinopathies, kidney disease, chronic inflammation, heart failure and myelodysplastic syndromes and is an independent predictor of overt stroke, white matter damage, and cognitive dysfunction. While anemia can be treated, the threshold for treatment is not well defined and many patients with chronic anemia go untreated because it is generally thought to be well tolerated. The goal of this study is to investigate the links between chronic anemia and neurological deficits using multimodal in-vivo imaging and neurocognitive data in human patients with chronic anemia syndromes(sickle cell disease and thalassemia syndromes) and race- and age-matched control subjects. Preliminary analysis presented in this proposal has shown that patients thought to have mild or adequately treated anemia may be suffering from neurologic damage, even those with morphologically normal hemoglobin. Our laboratory has demonstrated that cerebral blood flow is increased to maintain oxygen delivery at rest in anemic patients, but leaves patients with low cerebral vascular reserve, making them more vulnerable to ischemic insults. Additionally, preliminary analysis has demonstrated that anemia is associated with preclinical white matter injury in watershed regions having the lowest cerebral vascular reserve. Spatially, these regions lie diffusely throughout the brain but especially along the pathways of long-range fiber tracts and late-maturing gyri. To better interpret the pattern of injury, we propose using connectome analysis that allows us to perform whole brain connectivity analysis organized into biologically meaningful functional networks. Specific Aim 1 will use functional and structural connectome analysis to test whether network connectivity strength within late- maturing, heteromodal networks is selectively decreased in response to chronic anemia. Long-range fiber tracts and late maturing networks are essential for integrative cognitive processing, creating a logical link between anemia and the executive dysfunction commonly found in the elderly and in chronic anemia syndromes. Specific Aim 2 will specifically probe the association between our functional and structural connectome findings and neurocognitive performance. Altogether, the observed findings of chronic anemia's effect on brain connectivity and cognitive function may provide us with early biomarkers of neurological dysfunction in these patients. Additionally, understanding the possible neurological consequences of chronic anemia may inform under what clinical circumstances anemia should be more aggressively managed.